Stimulant treatment of adult attention-deficit/hyperactivity disorder

Psychiatr Clin N Am

27 (2004) 361–372

Stimulant treatment of adultattention-deficit/hyperactivity disorder

Thomas Spencer, MDa,b,*, Joseph Biederman, MDa,b,Timothy Wilens, MDa,b

aPediatric Psychopharmacology Unit, Massachusetts General Hospital, WACC 725,

15 Parkman Street, Boston, MA 02114, USAbHarvard Medical School, Boston, MA, USA

To develop treatment guidelines for the stimulant treatment of adults, theauthors reviewed the available literature of medication trials in attention-deficit/hyperactivity disorder (ADHD), attentive to issues of psychiatriccomorbidity, age, gender, and ethnic background [1]. The review showedstimulants to be the most established treatment for ADHD. Over 100controlled studies with more than 5000 children and adolescents havedocumented their efficacy in about 70% of subjects. The literature clearlydocuments that stimulants not only improve abnormal behaviors ofADHD, but also self-esteem, cognition, and social and family functioning.Efficacy varied with age and psychiatric comorbidities, however. In addi-tion, most studies have focused on latency age Caucasian boys. Little isknown about other subgroups. Most of the existing studies are very brief,lasting a few weeks at most, with until recently [2,3]. A very limited litera-ture exists for stimulants at other ages, for females [4–6] and for ethnicminorities [7].

A potential barrier to therapeutics is the increasing recognition thatADHD is a heterogeneous disorder with considerable comorbidity withconduct, mood, and anxiety disorders [8] and tic disorders [9]. It is not clearif these groups respond preferentially to different psychotropics. Forexample, an emerging literature suggests that anxious and depressedchildren with ADHD respond more poorly to stimulants than childrenwith only ADHD in their ADHD symptoms [10–14]. In addition, stimulantsare thought to be anxiogenic and depressogenic; however, the effect ofstimulants on the comorbid anxiety and depression symptoms has beenassessed rarely in any study. Although stimulants may be depressogenic, it is

* Corresponding author.

0193-953X/04/$ - see front matter � 2004 Elsevier Inc. All rights reserved.

doi:10.1016/j.psc.2003.12.002

362 T. Spencer et al / Psychiatr Clin N Am 27 (2004) 361–372

possible that demoralization and failure because of ADHD may improvewith stimulants by improving performance in the affected ADHD patient.

Despite the volume of juvenile ADHD research, little is known aboutthe effectiveness of stimulants and the prognostic value of psychiatriccomorbidity for ADHD in adults. In contrast to more than 100 controlledstudies evaluating the efficacy of stimulants in children and adolescents withADHD, there are only six controlled studies assessing the efficacy ofmethylphenidate (MPH) in adults with ADHD [15–20] and two controlledtrial of amphetamines in adults with ADHD [21,22]. Although the studies ofMPH in children and adolescents consistently report robust effects in theimprovement of symptoms of ADHD, equivocal results have been reportedin the trials of MPH in adults with this disorder. Among the four earlystudies of MPH in adults with ADHD, the average rate of response was50%, much lower than the 70% rate among children and adolescents [1].

The reasons for the difference in stimulant response between child andadult patients with ADHD are unknown. Plausible reasons include in-sufficient dosing, uncertain diagnostic criteria, and lack of attention toissues of psychiatric comorbidity. For example, the estimated mean dailyweight-corrected dose of MPH in the available studies of adult ADHDpatients was 0.6 mg/kg per day. This dose is much lower than the 1 mg/kgper day commonly used in the treatment of children with this disorder [1].Thus, it is possible that more aggressive pharmacotherapy of adult patientscould result in a more positive outcome than that reported in the literature.In addition, of four studies showing a poor or less than robust MPHresponse, two used Utah criteria [16,17], and one included patients withouta clear history of childhood-onset symptoms [15]. These latter studies didnot examine psychiatric comorbidity as a predictor of treatment response.

Methylphenidate treatment [20]

This investigation was a randomized, placebo-controlled crossover studyof MPH in 23 adult patients with Diagnostic and Statistical Manual ofMental Disorders, Revised Third Edition (DSM-III-R)-defined ADHD.The aim of the study was to assess the efficacy of MPH for treating ADHDsymptoms and those of comorbid disorders by using standardized instru-ments of diagnosis, paying careful attention to comorbidity with separateassessment of ADHD, depressive, and anxiety symptoms, and administeringa robust daily dose of up to 1.0 mg/kg per day (Table 1).

Subjects were adults who were referred clinically with the diagnosis ofDSM-III-R-defined ADHD. They were ascertained from clinical referrals tothe Adult and Pediatric Psychopharmacology Units of the MassachusettsGeneral Hospital who met study inclusion criteria. Outpatients of either sexbetween 18 and 55 years of age were eligible for entry into the study if theymet DSM-III-R criteria for a diagnosis of childhood-onset ADHD as mani-fested in clinical evaluation and confirmed by structured interview.

363T. Spencer et al / Psychiatr Clin N Am 27 (2004) 361–372

Exclusion criteria included any clinically significant chronic medicalcondition (including serious hypertension (defined as any values above 100diastolic and 170 systolic), clinically significant abnormal baseline labora-tory values, a history of seizures, being pregnant or nursing, having a historyof tics, mental retardation (IQ less than 75), organic brain disorders,clinically unstable psychiatric conditions (ie, suicidal behaviors or psycho-sis), current (within the past 6 months) substance (drug or alcohol) abuse ordependence, or current use of psychotropic agents (Fig. 1).

Each patient participated in a balanced, 7-week, double-blind, placebo-controlled, cross-over study design. The study consisted of two 3-weektreatment periods, with 1 week of washout in between. Medication (MPH orplacebo) was titrated from an initial dose of 0.5 mg/kg per day at week 1, to0.75 mg/kg per day at week 2, and 1.0 mg/kg per day at week 3 as tolerated.Assessments were conducted weekly using several instruments. The ClinicalGlobal Impression (CGI) Scale [23] assessed overall severity and globalimprovement in each of the three domains of psychopathology (CGI-ADHD, CGI-anxiety, and CGI-depression). The ADHD Rating Scale

Table 1

Description of sample (N = 23)

Mean age (� SEM) (range) 40 � 2.1 (19–56)

Males (N (%)) 10 (43%)

Diagnosis (%)a

Attention-deficit/hyperactivity disorder 23 (100%)

Mood disorder 6 (26%)

Anxiety disorder 9 (39%)

Antisocial personality 1 (4%)

Substance abuse 5 (22%)

No comorbid diagnosis 6 (26%)

a Patients can have more than one diagnosis.

(Adapted from Spencer T, Wilens T, Biederman J, Faraone SV, Ablon JS, Lapley K. A

double-blind, cross-over comparison of methylphenidate and placebo in adults with childhood-

onset attention-deficit/hyperactivity disorder. Arch Gen Psychiatry 1995;52:434–43.)

Fig. 1. Study design. (Adapted from Spencer T, Wilens T, Biederman J, Faraone SV, Ablon JS,

Lapley K. A double-blind cross-over comparison of methylphenidate and placebo in adults with

childhood-onset attention-deficit/hyperactivity disorder. Arch Gen Psychiatry 1995;52:434–43.)


[24,25] assessed ADHD symptoms. The Hamilton Depression Scale (HAM-D) [26] and the Beck Depression Inventory [27] assessed depressivesymptoms. The Hamilton Anxiety Scale (HAM-A) [28] assessed anxietysymptoms. Medication was administered three times daily.

Twenty five subjects enrolled in the study, and 23 (92%) completed it.The two subjects who dropped out, one male and one female, were both onMPH. One had an episode of chest pain in the third week of the trial whileon a dose of 1 mg/kg per day of MPH. Although dropped from the study,he elected to have further treatment with MPH after consultation withhis internist. The second patient dropped out in the first week because ofagitation, irritability, and general unease. Because these two dropout casesdid not complete the treatment protocol, they are not included in the dataanalysis. Thus, the final sample consisted of 13 women and 10 men whoranged in age from 19 to 56 years (mean � SEM = 40 � 2 years). All metfull criteria for a DSM-III-R diagnosis of ADHD with at least 8 of 14symptoms (DSM-III-R) and an onset of the clinical picture in childhood bythe age of 7 years. In all cases, the disorder was continuous until the time ofassessment and associated with significant distress and disability. Only onesubject had been diagnosed in childhood with ADHD, and none had beentreated previously. As depicted in Table 1, 74% (N = 17) of ADHDsubjects had at least one past comorbid psychiatric disorder. For 59%(N = 13) of the sample, the comorbid disorder was current. The averagenumber of comorbid diagnoses was 2.6 plus or minus 0.3 per subjects.Baseline ratings of depression (HAM-D = 5.6 � 1.1 and Beck 8.6 � 1.6)and anxiety (HAM-A = 5.7 � 1.0) symptoms were relatively low. Usingstandard cut-off points for moderate severity on ratings of depression(HAM-D greater than 16; Beck Depression Inventory greater than 19) andanxiety (HAM-A greater than 21), only 9% of subjects had scores ofdepression or anxiety above those cut-off points.

Methylphenidate treatment was more effective than placebo after the firstweek of treatment, and improvement was increasingly robust in subsequentweeks with increases in daily doses (see Fig. 1). Analysis of the ADHDRating Scale (transformed) data by multivariate analysis of variance(MANOVA) showed highly significant effects for ADHD symptoms forthe effects of drug (MPH or placebo; F[1,22] = 36, P = 0.0001), time(weeks 0,1,2,3; F[3,20] = 11, P = 0.0002), and the drug-by-time interaction(F[3,20] = 12, P = 0.0001). In addition, the MANOVA for ADHD symp-toms found no significant order effect (MPH first versus placebo first),no significant two-way interaction between drug and MPH order, and nosignificant three-way interaction between drug, weeks, and order. Theauthors’ analyses of the ADHD severity score produced a similar pattern ofresults (Fig. 2).

In contrast to the significant findings for ADHD, none were found fordepression or anxiety by any of the study measures. To evaluate further theabsolute rate of improvement in this sample, the authors analyzed end-


of-treatment results using their pre-established definition of improvement,defined as a subject attaining a score of two or better (much or very muchimproved) on the CGI and a reduction of at least 30% in individual ratingscales. Because of the scarcity of subjects with current depressive or anxiety,the authors could not evaluate the impact of treatment on these domainsby this method of comparison. Seventy-eight percent (18/23) of patientshad meaningful improvement in ADHD symptoms while on MPH, com-pared with only 4% (1/23) on placebo (X2 = 25.91, df = 1, P\0.0001).These results did not change when data were analyzed after stratificationby order of randomization (MPH first, placebo second: X2 = 17.14, df = 1,P\0.0001; placebo first, MPH second: X2 = 9.21, df = 1, P = 0.0039). Toevaluate the effects of treatment on individual ADHD symptoms and clustersof ADHD symptoms (inattentive, hyper, and impulsive), data on thesevariables also were examined. This analysis showed highly significant dif-ferences betweenMPH and placebo for reduction of each of the 14 symptomsof ADHD (P\0.001) (Fig. 3).

Results also were evaluated after stratification by sociodemographiccharacteristics, past history of comorbidity (lifetime), and family history ofpsychopathology to examine the role of these factors as potential confoundsin accounting for the study findings. These analyses showed that equallyrobust responses to MPH could be established after stratification of subjectsby these variables (Table 2). Although similarly robust responses to MPHwere observed in subjects with and without major depression, conductdisorder, or substance use disorders, there was insufficient statistical powerto fully evaluate the impact of treatment on these subgroups (see Table 2).

Fig. 2. Attention-deficit/hyperactivity rating scale scores. (Adapted from Spencer T, Wilens T,

Biederman J, Faraone SV, Ablon JS, Lapley K. A double-blind cross-over comparison of

methylphenidate and placebo in adults with childhood-onset attention-deficit/hyperactivity

disorder. Arch Gen Psychiatry 1995;52:434–43.)


Correlation analysis revealed no meaningful associations between improve-ment of symptoms of ADHD and age, number of ADHD symptoms,severity scores, and ratings of depression or anxiety (all rs � 0.30).

Treatment generally was tolerated well; only three subjects (13%) wereunable to tolerate the target dose of 1.0 mg/kg per day. Although the ratesof subjective adverse effects did not differ between MPH and placebo, theywere more pronounced on active medication. The most common adverseeffects were loss of appetite, insomnia, and anxiety. Five subjects on MPHbut no subject on placebo had the dose lowered because of adverse effects.Reasons for dose reduction included anxiety (N = 3), insomnia (N = 2),and euphoria (N = 1). Although no meaningful changes in blood pressurewere observed between MPH or placebo conditions (systolic, 123 � 2.6versus 117 � 1.7 mm Hg; diastolic 77 � 2.0 versus 75 � 1.5 mm Hg), a smallbut statistically significant increase in heart rate (80 � 2.4 versus 76 � 1.5beats per minute) and decrease in weight (162.6 � 7.6 versus 165.2 � 7.9 lb)were observed on MPH but not on placebo. None of these findings wereclinically significant, however, and no subject required altering the dose ofmedication as a consequence.

This study supported the hypothesis that robust MPH treatment (0.92mg/kg per day) is efficacious in the treatment of ADHD symptoms andthat the response in adults may be dose-dependent, consistent withdose-dependent cognitive, behavioral, and academic improvements seen inchildren [1]. The overall response rate for ADHD symptoms was clinicallyand statistically higher during MPH treatment than during placebo treat-

Fig. 3. Controlled study of methylphenidate in adults with attention-deficit/hyperactivity

disorder. (Adapted from Spencer T, Wilens T, Biederman J, Faraone SV, Ablon JS, Lapley K. A

double-blind cross-over comparison of methylphenidate and placebo in adults with childhood-



ment (78% versus 4%; P\ 0.0001). Although this study did not haveadequate power to examine the effects of comorbidity on outcome, MPHdid not appear to benefit depression or anxiety symptoms. Improvement inADHD symptoms was independent of gender, psychiatric comorbidity withanxiety or moderate depression, or family history of psychiatric disorders.

National Institute of Mental health study of methylphenidate treatment

(preliminary results)

Recently, Spencer et al [29] reported preliminary results of an ongoingdouble-blind, placebo-controlled, parallel study of MPH in adults withADHD. This is a 6-week, randomized, double-blind, placebo-controlledtrial of MPH in well-characterized adults satisfying full Diagnostic andStatistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteriafor ADHD of childhood onset and persistent symptoms into adulthood.The interim analysis included 103 adults. Medication was titrated up to 1.3mg/kg per day over 6 weeks. Outcome measures included the ADHD RatingScale and the Clinical Global Impression Score. Comorbid psychiatricdisorders were assessed to test for potential effects on treatment outcome.Treatment with MPH at an average oral dose of 82 mg (administered inthree daily doses) was effective and well tolerated. Drug-specific improve-ment in ADHD symptoms was highly significant overall (43% decrease on

Table 2

Improvement stratified by gender and comorbidity

Stratification MPH Placebo

N % %

Gender

Male 10 80a

Female 13 77c

Comorbid disorders

+Major depression 6 67 0

�Major depression 16 82c 6

+Multiple (�2) Anxiety disorders 9 67a 0

�Multiple (�2) Anxiety disorders 13 86c 7

+Conduct disorder 3 67 33

�Conduct disorder 19 80c 0

+Substance abuse 5 60 0

�Substance abuse 17 83c 6

+Learning disability 8 100c 0

�Learning disability 14 71c 0

a pS0.01.b pS0.001.c pS0.0001 by v2 analysis.(Adapted from Spencer T, Wilens T, Biederman J, Faraone SV, Ablon JS, Lapley K. A

double-blind cross-over comparison of methylphenidate and placebo in adults with childhood-



the ADHD Rating Scale, P \ 0.001). The proportion of subjects whoimproved (reduction in the ADHD rating scale of �30% and a CGI of 1or 2) was significantly higher with MPH treatment than with placebo(73% versus 23%; P=0.001). The investigators concluded that MPH waseffective and well tolerated in the short-term treatment of adults withADHD. The magnitude of response of the previous, pilot study wasreplicated in a larger study. In addition, patient satisfaction was improved inmultiple domains. Because this is a study in progress, however, definitiveconclusions await the final analysis.

Pemoline

Previous studies with the long-acting stimulant magnesium pemoline(Cylert) have been equivocal with one very small open study not dem-onstrating efficacy [15] and one controlled study only showing efficacy whenassessing those with childhood-onset disorder [30]. In those studies,however, the dosing of pemoline was relatively low (less than 75 mg perday); the diagnosis was not always anchored in childhood, and the presenceof comorbidity was not evaluated. The authors recently reported findings ofan ongoing double-blind, placebo controlled, cross-over design study of theuse of pemoline at doses of 3 mg/kg per day for adults with ADHD [31].

The authors conducted a 10-week, double-blind, placebo-controlled, cross-over design study of pemoline at a target daily dose of 3 mg/kg per day in35 adult patients with DSM-IIIR- and IV-defined ADHD. As with themethylphenidate study, the authors used standardized structured psychiatricinstruments for diagnosis and separate assessments of ADHD, depressive,and anxiety symptoms. The study consisted of two 4-week treatment periodsin which subjects received either placebo or pemoline, separated by a 2-weekplacebo washout phase. During the 4-week medication/placebo phases,pemoline or placebo was titrated up to 1 mg/kg per day in week 1 (circa 75 mgper day), to 2mg/kg per day byweek 2 (circa 150mg), 3mg/kg per day byweek3 (maximal dosing, circa 225 mg), and dosed flexibly in week 4 (less than orequal to 3 mg/kg per day), unless adverse effects emerged.

Of the 35 adults with ADHD randomized in the trial, 27 (77%) com-pleted the protocol. Treatment with pemoline in the final week of theactive phase was tolerated best at doses substantially lower than the targetdose of 3 mg/kg per day (mean � SD, 2.2 mg/kg per day; 148 � 95 mg).Pemoline was significantly better at reducing ADHD symptoms comparedwith placebo (Z = 2.4, P \ 0.02). Using a predefined 30% reduction insymptoms, 50% of pemoline-treated subjects and 17% of subjects in theplacebo group were considered positive responders (X 2 = 7.1, P = 0.008).As in the MPH trial, most ADHD subjects had at least one past comorbidpsychiatric disorder, with anxiety, mood, and substance use disorders mostfrequent. Baseline ratings of depression and anxiety were relatively low,


however. Response to pemoline was independent of dose, gender, or lifetimepsychiatric comorbidity.

These results indicate that pemoline is moderately effective in thetreatment of ADHD in adults. Although robust doses were targeted, mostadults preferred more moderate dosing (120 to 160 mg per day). The currentpreliminary findings suggest that the magnitude of the anti-ADHD responsewith pemoline is less than that reported in adults with ADHD receiving1 mg/kg per day of methylphenidate (ca, 30% vs. 57% reduction in symp-toms). Recent reports of serious idiosyncratic hepatic reactions to pemolinein children have led to important restrictions in its use. Given the limitedefficacy, tolerability, and concerns of hepatic dysfunction, pemoline shouldbe considered as second-line medication in adults with ADHD.

Amphetamine

Using a similar design to the pilot MPH study, Spencer et al [22] reportedon a controlled trial of a mixed amphetamine salts compound (Adderall,dextroamphetamine sulfate, dextro-, levoamphetamine sulfate, dextro-,levoamphetamine aspartate, and dextroamphetamine saccharate) in thetreatment of adults with ADHD. Adderall consists of 25% levo- and 75%dextroamphetamine in four salts. The Adderall study in adults with ADHDwas a 7-week, randomized, double-blind, placebo-controlled, cross-overdesign in 27 well-characterized adults satisfying full DSM-IV criteria forADHD of childhood onset and persistent symptoms into adulthood.Adderall was titrated up to 30 mg twice daily. Outcome measures includedthe ADHD Rating Scale and the Clinical Global Impression Score.Comorbid psychiatric disorders were assessed to test for potential effectson treatment outcome. Results showed that treatment with Adderall at anaverage oral dose of 54 mg (administered in two daily doses) was highlyeffective and well tolerated. Drug-specific improvement in ADHD symp-toms was highly significant overall (42% decrease on the ADHD RatingScale, P\ 0.001), and sufficiently robust to be detectable in a parallel groupcomparison restricted to the first 3 weeks of the protocol (P\ 0.001). Theproportion of subjects who improved (reduction in the ADHD rating scaleof greater than or equal to 30%) was significantly higher with Adderalltreatment than with a placebo (70% versus 7%; P = 0.001) (Fig. 4).

Adderall was tolerated well, and no serious adverse effects were observed.Of individual adverse effects reported, only Adderall-associated appetitesuppression and agitation reached the authors’ threshold for statisticalsignificance. All patients who received active medication completed thestudy. A statistically significant but a clinically small difference was observedwith Adderall treatment in diastolic blood pressure (76 versus 71 mm ofHg, t = 2.6, df (25), P\ 0.05). Although weight decreased an average of 4pounds (167 versus 163 pounds, t = 5.8, df (25), P\0.001), weight loss was


not of clinical significance in any individual patient. This study documentsthat Adderall was effective and tolerated well in the short-term treatment ofadults with ADHD.

Multisite trial of amphetamine

Preliminary results of a controlled, multi-site trial of an extended releaseform of a mixed amphetamine salts compound (Adderall XR) were reportedin the treatment of adults with ADHD [32]. The assessment methodologyand dosing were extrapolated from the single-site mixed amphetamine saltstrial. This was a randomized, double-blind, forced-dose titration study thatassessed the efficacy and safety of Adderall XR (20, 40, or 60 mg once daily)compared with placebo in 255 adults with a diagnosis of ADHD. Patientsmet DSM-IV criteria for ADHD and also had to have a history of ADHDbefore age 7. The intent-to-treat population included 248 subjects (mean age39 years). Primary efficacy was assessed using the 18-item ADHD RatingScale (ADHD-RS) for adults. Mean ADHD-RS total scores for eachtreatment group ranged from 31.1 to 33.0 at baseline. At study endpoint, alldoses of Adderall XR significantly reduced mean ADHD-RS total scorescompared with placebo: 19.2 for 20 mg, 18.6 for 40 mg, and 18.0 for 60 mgcompared with 25.5 for placebo (P\ 0.001 for all doses). Safety measureswere performed throughout the 6-week study. The most commonly reportedadverse events were dry mouth (27.5%), anorexia (25.5%), insomnia(23.5%), headache (22.7%), and nervousness (12.5%), and these wereconsistent with those noted in pediatric patients. The authors concluded

Fig. 4. Adderall study for attention-deficit/hyperactivity disorder in adults. First 4 weeks.

DSM-IV ADHD Symptom Checklist. (Adapted from Spencer T, Biederman J, Wilens T,

Faraone SV, Prince J, Gerand K, et al. Efficacy of mixed amphetamine salts compound in

adults with attention-deficit/hyperactivity disorder. Arch Gen Psychiatry 2001;58:775–82.)


that Adderall XR administered in once daily doses of 20, 40, or 60 mgappears to be safe and efficacious for treating adults with ADHD.

Summary

Though only recently recognized as a valid disorder in adults, theclinical picture of adult ADHD is highly reminiscent of childhood ADHD,with continued associated occupational failure and academic deficits.Similarly, many adults with ADHD suffer from antisocial, depressive, andanxiety disorders. Recent work clearly documents that when therapeuticdoses of MPH and amphetamine treatment are used in the treatment ofadults with ADHD, they can lead to a robust clinical response that is highlyconsistent with that observed in pediatric studies using equipotent dailydoses. As in childhood ADHD, medication remains a key component oftreatment for adults with ADHD. More studies are needed to evaluate theefficacy and safety of stimulants over the long-term and their impact onquality of life.

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Stimulant treatment of adult attention-deficit/hyperactivity disorder